title: Intrinsically unstructured proteins by design-electrostatic interactions can control binding, folding, and function of a helix-loop-helix heterodimer.
abstract: Intrinsically disordered proteins that exist as unordered monomeric structures in aqueous solution at pH 7 but fold into four-helix bundles upon binding to recognized polypeptide targets have been designed. NMR and CD spectra of the monomeric polypeptides show the hallmarks of unordered structures, whereas in the bound state they are highly helical. Analytical ultracentrifugation data shows that the polypeptides bind to their targets to form exclusively heterodimers at neutral pH. To demonstrate the relationship between binding, folding, and function, a catalytic site for ester hydrolysis was introduced into an unordered and largely inactive monomer, but that was structured and catalytically active in the presence of a specific polypeptide target. Electrostatic interactions between surface-exposed residues inhibited the binding and folding of the monomers at pH 7. Charge-charge repulsion between ionizable amino acids was thus found to be sufficient to disrupt binding between polypeptide chains despite their inherent propensities for structure formation and may be involved in the folding and function of inherently disordered proteins in biology.
authors.affiliation: Department of Chemistry-IFM, Linköping University, 581 83, Linköping, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Rydberg
authors.forename: Lars
authors.initials: L
authors.lastname: Baltzer
authors.forename: Vijayalekshmi
authors.initials: V
authors.lastname: Sarojini
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D064267:Intrinsically Disordered Proteins / Q000737:chemistry*; D007700:Kinetics; D008969:Molecular Sequence Data; D011485:Protein Binding; D015202:Protein Engineering; D017510:Protein Folding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary
chemical_list: D064267:Intrinsically Disordered Proteins
keywords: catalysis; electrostatic interactions; folding; heterodimer